Abstract & Commentary
Synopsis: In hypertensive patients without clinically evident vascular disease, losartan was more effective than atenolol in preventing future vascular events independent of blood pressure control.
Source: Dahlof B, et al. Lancet. 2002;359:995-1003.
The Losartan Intervention For Endpoint reduction (LIFE) in hypertension study has shown that this angiotensin receptor antagonist reduced cardiovascular morbidity and mortality vs therapy with the beta-blocker atenolol. Two substudy reports are now available that shed further light on this interesting investigator-initiated trial.
The first is a subgroup analysis of 6886 hypertensive patients with left ventricular hypertrophy by ECG, but without clinical evidence of coronary, cerebral, or peripheral vascular disease. After 1-2 weeks of placebo, if blood pressure was 160-200/95-115 mm Hg, they were randomized to once-daily, double-blind administration of losartan or atenolol titrated to lower blood pressure to < 140/90 mm Hg. The primary end point was a composite of cardiovascular death, stroke, or myocardial infarction (MI) over 4 or more years of follow-up. The patients were mainly white (93%), and few were smokers (15%), diabetics (11%), or had isolated systolic hypertension (13%). Hydrochlorothiazide could be added if necessary to reach target blood pressures and was done so in about half of the patients. Other drugs could be added if the combination with hydrochlorothiazide was not sufficient, and almost 40% were also on calcium channel blockers. Losartan and atenolol doses ranged from 50-100 mg (mean, 80 mg for both). Adherence to study drug over the follow-up time was 86% for losartan and 82% for atenolol. Both groups experienced similar reductions in blood pressure. The primary end point occurred in 17.5/1000 patient-years with losartan vs 21.8 for atenolol (relative risk [RR], 0.81; 95% CI, 0.69-0.95; P = .008). When the individual components of the combined end point were examined, only stroke was significantly reduced on losartan vs atenolol (RR, 0.66; CI, 0.53-0.82; P < .001). Cardiovascular death and myocardial infarction were not. Also of interest, new-onset diabetes occurred less often in the losartan patients (RR, 0.69; CI, 0.57-0.84; P < .001). Dahlof and associates concluded that in hypertensive patients without clinically evident vascular disease, losartan was more effective than atenolol in preventing future vascular events independent of blood pressure control.
Comment by Michael H. Crawford, MD
This study extends the observations of the Heart Outcomes Prevention Evaluation (HOPE) trial, which showed, in a high risk for vascular disease population, that the ACE inhibitor ramapril reduced a composite cardiovascular end point vs placebo, independent of the effects on blood pressure. This study is impressive because the control group was atenolol therapy. Beta-blockers have been shown to reduce cardiovascular end points in hypertension, post-MI, and other vascular disease patients. For example, in the Swedish Trial in Old Patients (STOP) with hypertension, beta-blockers including atenolol reduced the primary composite cardiovascular end point by 40% vs placebo plus diuretics. In this study, fatal and nonfatal strokes were reduced 34% by losartan as compared to atenolol therapy. The incidence of MI was not different between the 2 therapies, so beta-blockers were not superior to losartan. The results suggest that the vasotoxic effects of the reninangiotensin system are more important than the adrenergic system in hypertensive patients without clinically evident vascular disease. Also, there was a lower incidence of new-onset diabetes with losartan vs atenolol.
Overall, it would appear that a drug that blocks the renin-angiotensin system should be part of the antihypertensive regimen of such high-risk patients as those with left ventricular hypertrophy. There were some limitations to this study that temper the conclusions. This was a subgroup analysis, although a big one since 75% of the patients in LIFE qualified for this analysis. Nevertheless, subgroup analyses often lack the power to detect small differences or large ones with events that occur less frequently such as death. Almost all the patents were white, so the results may not apply to other groups. Also, this was a high-risk subgroup since all the patients had ECG evidence of left ventricular hypertrophy, a known poor prognostic factor. Although the study was designed to be double blind, it is impossible to make a study involving beta-blockers double blind. The physicians know who is on beta-blocker by observing heart rate changes and so do the patients if they read the consent form and take their own pulse. What effect this had on the study results is uncertain, but the potential for bias exists. Finally, there is the issue of whether this is an effect unique to losartan, a class effect of all angiotensin receptor blockers (ARBs), or even includes ACE inhibitors. Given the HOPE results, most are assuming that the benefits observed would apply to ARBs and ACEIs, but this may not be correct.
Dr. Crawford, Professor of Medicine, Associate Chief of Cardiology for Clinical Programs, University of California, San Francisco, is Editor of Clinical Cardiology Alert.